Summary of work: Normal aging is associated with loss of lean body and muscle mass and strength. There are also increases in body fat, deterioration in lipid profiles and glucose intolerance (risk factors for heart diseasse) and reductions in cardiac function and fitness, immune function, and skin thickness. Reductions in sex steroid hormones, testosterone (T) in men and estradiol (E2) in women as well as growth hormone (GH) and its primary messenger, insulin like growth factor I (IGF-I), with age appear to contribute to these changes in body composition. Cortisol, the major steroid secreted by the adrenal gland generally opposes the actions of GH and may increase somewhat with age. Prior studies have shown partial reversal of age-related changes in lean body and fat mass, skin thickness, and certain metabolic variables when rhGH was given to older persons. Work in our laboratory has demonstrated improved muscle strength, lipoprotein patterns, blood pressure, and glucose tolerance in men over 65 years of age treated with GH releasing hormone. Current studies examine the effects of GH and sex steroid hormone replacement, alone and combined, on body composition, skeletal muscle (strength, biochemistry, molecular biology), bone biochemistry, glucose and lipid metabolism, measures of gonadal, immune, renal, and cardiac function, quality of life and psychological and sexual variables in healthy men and women over 65 years of age over a 6 month period. Recently we have added measurements of plasma leptin, a hormone secreted by fat cells which influences satiety and energy metabolism, and of arterial compliance. As of 8/15/97, 109 subjects have entered the study, 95 have completed, 6 have dropped out and 8 are active. Because treatment groups remain masked, analyses to study domains at baseline. We have recently investigated the extent to which plasma leptin levels are independently related to body fat and to endocrine-metabolic correlates of body fat in the elderly. Leptin levels and % total fat were greater in women vs men, and leptin was highly correlated with measures of fat in both sexes. Leptin was related inversely to GH secretion in both women and men, but was not significantly related to age or other hormone or metabolic variables in either sex. Moreover, the gender difference in leptin and its relationships with GH were completely accounted for by the variation in % total fat. These data suggest that in healthy elderly individuals, plasma leptin levels are a function of adiposity per se, but not of age, sex or other endocrine-metabolic factors. We have also examined the relationships of GH and cortisol secretion in our study population using deconvolution analysis, a unique mathematical technique for assessing hormone secretion rates. As part of this effort, we assessed approximate entropy (ApEn), a measure of the orderliness of hormone release. We found that half-life of GH was longer, and mean and integrated GH secretion were greater, in women vs. men. The frequency of cortisol secretory bursts, its production rate, and the total cortisol secretion were also greater in women. The half-life of cortisol and the interval between bursts of cortisol secretion were longer in men. There was no gender difference in ApEn for GH, whereas the ApEn for cortisol secretion was higher (i.e. more disorganized) in women. We observed a direct relationship of cortisol secretion to the mass of GH secreted per burst and hence to GH production rate but no relationhship of cortisol with GH half-life or GH interburst interval. Our findings that in healthy older women vs men cortisol secretion is greater, less orderly, and enhances GH secretion by increasing the GH secretory mass/burst and that cortisol (at normal physiological concentrations) appears to enhance GH secretion provide new insights into hormone physiology in the elderly. The coupling of cortisol to GH secretion suggests that the body may compensate for potential deleterious effects of cortisol on body composition by an increase in GH production. These studies are aimed at understanding (a) the potential clinical utility of interventions with GH and/or sex steroid hormones and (b) the cellular, biochemical, and molecular events responsible for, and resulting from, altered secretion of these hormones with age. Such investigations may lead to novel therapies to delay or ameliorate the deleterious effects of aging on the musculoskeletal system and other systems which contribute to frailty and loss of mobility in the elderly. We propose to continue vigorous recruitment efforts in order to meet the requirements of the study timetable. Analysis of baseline data including MRI and DEXA measurements and measures of cardiac function will continue through FY '98. Treatment data will be analyzed in early to mid-FY '99. New studies are being planned, investigating the effects of an oral GH stimulating agent (GHRP analogue) on bone in osteoporotic women and men and on cardiovascular risk factors and cardiovascular function in older men and women with and without heart disease.